CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice

Young Sun Kang, Mi Hwa Lee, Hye Kyoung Song, Gang Jee Ko, Oh Sung Kwon, Tae Kyung Lim, Sung Hwan Kim, Sang Youb Han, Kum Hyun Han, Ji Eun Lee, Jee Young Han, Hyoung Kyu Kim, Dae Ryong Cha

    Research output: Contribution to journalArticlepeer-review

    98 Citations (Scopus)


    Chemokine ligand 2 (CCL2) binds to its receptor C-C chemokine receptor 2 (CCR2), initiating tissue inflammation, and recent studies have suggested a beneficial effect of a blockade of this pathway in diabetic nephropathy. To investigate the mechanism of protection, we studied the effect of RS504393, a CCR2 antagonist, on insulin resistance and diabetic nephropathy in db/db mice. Administering this antagonist improved insulin resistance as confirmed by various biomarkers, including homeostasis model assessment index levels, plasma insulin levels, and lipid abnormalities. Mice treated with the antagonist had a significant decrease in epididymal fat mass as well as phenotypic changes of adipocytes into small differentiated forms with decreased CCL2 expression and lipid hydroperoxide levels. In addition, treatment with the CCR2 antagonist markedly decreased urinary albumin excretion, mesangial expansion, and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, the CCR2 antagonist improved lipid metabolism, lipid hydroperoxide, cholesterol, and triglyceride contents of the kidney, and decreased urinary 8-isoprostane levels. Hence, our findings suggest that CCR2 antagonists can improve insulin resistance by modulation of the adipose tissue and restore renal function through both metabolic and anti-fibrotic effects in type 2 diabetic mice.

    Original languageEnglish
    Pages (from-to)883-894
    Number of pages12
    JournalKidney International
    Issue number9
    Publication statusPublished - 2010 Nov

    Bibliographical note

    Funding Information:
    This work was supported by a grant from the Brain Korea 21 project and a special grant from Korea University.


    • HOMA-IR
    • LPO
    • MCP-1
    • renal lipid metabolism

    ASJC Scopus subject areas

    • Nephrology


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